The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D. R. Lowy and D. M. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a xe2x80x9cCAAXxe2x80x9d or xe2x80x9cCys-Aaa1-Aaa2-Xaaxe2x80x9d box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386 (1992); W. R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237 (1992)). The term prenyl-protein transferase may be used to generally refer to farnesyl-protein transferase and geranylgeranyl-protein transferase. The Ras protein is one of several proteins that are known to undergo post-translational farnesylation. Other farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly (N. E. Kohl et al., Science, 260:1934-1937 (1993) and G. L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of ras-dependent tumors in nude mice (N. E. Kohl et al., Proc. Natl. Acad. Sci U.S.A., 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice (N. E. Kohl et al., Nature Medicine, 1:792-797 (1995).
Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck and Co., Rahway, N.J.) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA, 87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.
Inhibitors of farnesyl-protein transferase (FPTase) have been described in two general classes. The first are analogs of farnesyl diphosphate (FPP), while the second class of inhibitors is related to the protein substrates (e.g., Ras) for the enzyme. The peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Pat. No. 5,141,851, University of Texas; N. E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)). In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound. However, the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.
It has recently been reported that farnesyl-protein transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-112930).
It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitors of farnesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 A1).
It is, therefore, an object of this invention to develop peptidomimetic compounds that do not have a thiol moiety, and that will inhibit prenyl-protein transferase and thus, the post-translational prenylation of proteins. It is a further object of this invention to develop chemotherapeutic compositions containing the compounds of this invention and methods for producing the compounds of this invention.
The present invention comprises peptidomimetic macrocyclic compounds which inhibit the prenyl-protein transferase. Further contained in this invention are chemotherapeutic compositions containing these prenyl-protein transferase inhibitors and methods for their production.
The compounds of this invention are illustrated by the formula A: 
The compounds of this invention are useful in the inhibition of prenyl-protein transferase and the prenylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula A: 
wherein:
R1a, R1b, R1c, R1d and R1e are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, cycloalkyl, alkenyl, alkynyl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(O)xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, -N(R10)2, or R11OC(O)NR10xe2x80x94,
c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, halogen, R10Oxe2x80x94, R4S(O)mxe2x80x944S(O)2NR10xe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(O)xe2x80x94, CN, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, and R11OC(O)-NR10xe2x80x94;
or two R1as, two R1bs, two R1cs, two R1ds or two R1es, on the same carbon atom may be combined to form xe2x80x94(CH2)vxe2x80x94;
R4 is selected from C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO, 
f) xe2x80x94SO2R11,
g) N(R10)2, or
h) C1-4 perfluoroalkyl;
R6 and R7 are independently selected from:
1) hydrogen,
2) R10C(O)xe2x80x94, or R10OC(O)xe2x80x94, and
3) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, C6-C10 multicyclic alkyl ring, unsubstituted or substituted with one or more substituents selected from:
a) R10Oxe2x80x94,
b) aryl or heterocycle,
c) halogen,
d) R10C(O)NR10xe2x80x94, 
f) xe2x80x94SO2R11,
g) N(R10)2,
h) C3-6 cycloalkyl,
i) C6-C10 multicyclic alkyl ring,
j) C1-C6 perfluoroalkyl,
k) (R10)2Nxe2x80x94C(NR10)xe2x80x94,
l) R10OC(O)xe2x80x94,
m) R11OC(O)NR10xe2x80x94,
n) CN, and
o) NO2; or
R6 and R7 may be joined in a ring;
R8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R12Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, NO2, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NHxe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, or R10OC(O)NHxe2x80x94;
R9 is selected from:
a) hydrogen,
b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, NO2, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R10 is independently selected from hydrogen, C1-C6 alkyl, unsubstituted or substituted benzyl, unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
R11 is independently selected from C1-C6 alkyl unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C3 perfluoroalkyl, unsubstituted or substituted benzyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, and C1-C6 alkyl substituted with unsubstituted or substituted aryl or unsubstituted or substituted heterocycle;
A1 is selected from a bond, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94, and S(O)m;
A2 is selected from a bond, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94R10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94, S(O)m and xe2x80x94C(R1d)2xe2x80x94;
W is heteroaryl;
V is selected from:
a) heteroaryl, and
b) aryl;
X and Y are independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, xe2x80x94NR10C(O)-Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)NR10xe2x80x94, xe2x80x94C(O)NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94 and S(O)m;
Z1 is selected from unsubstituted or substituted aryl and unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or more of:
1) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) xe2x80x94S(O)mR4,
g) xe2x80x94C(O)NR6R7,
h) xe2x80x94Si(C1-4 alkyl)3, or
i) C1-4 perfluoroalkyl;
2) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3,
9) xe2x80x94S(O)mR4,
10) xe2x80x94OS(O)2R4,
11) xe2x80x94C(O)NR6R7,
12) xe2x80x94C(O)OR6, or
13) C3-C6 cycloalkyl;
Z2 is selected from a bond, unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl, wherein the substituted aryl or substituted heteroaryl is substituted with one or more of:
1) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) xe2x80x94S(O)mR4,
g) xe2x80x94C(O)NR6R7,
h) xe2x80x94Si(C1-4 alkyl)3, or
i) C1-4 perfluoroalkyl;
2) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3,
9) xe2x80x94S(O)mR4,
10) xe2x80x94OS(O)2R4,
11) xe2x80x94C(O)NR6R7,
12) xe2x80x94C(O)OR6, or
13) C3-C6 cycloalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 1 or 2;
r is 0 to 5;
s is independently 0, 1, 2 or 3;
t is 1, 2, 3 or 4; and
v is 2 to 6;
or a pharmaceutically acceptable salt or stereoisomer thereof.
In a second embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula A: 
wherein:
R1a, R1b, R1c, R1d and R1e are independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(O)xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94,
c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(O)xe2x80x94, CN, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, and R11OC(O)-NR10xe2x80x94;
R4 is selected from C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO, 
f) xe2x80x94SO2R11, or
g) N(R10)2;
R6 and R7 are independently selected from H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO, 
f) xe2x80x94SO2R11, or
g) N(R10)2; or
R6 and R7 may be joined in a ring;
R8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, NO2, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NHxe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, or R10OC(O)NHxe2x80x94;
R9 is selected from:
a) hydrogen,
b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, NO2, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
R11 is independently selected from C1-C6 alkyl unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
A1 is selected from a bond, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94, and S(O)m;
A2 is selected from a bond, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94, S(O)m and xe2x80x94C(R1d)2xe2x80x94;
W is heteroaryl;
V is selected from:
a) heteroaryl, and
b) aryl;
X and Y are independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, xe2x80x94NR10C(O)-Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)NR10xe2x80x94, xe2x80x94C(O)NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94 and S(O)m;
Z1 is selected from unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl, wherein the substituted aryl or substituted heteroaryl is substituted with one or more of:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) xe2x80x94S(O)mR4, or
g) xe2x80x94C(O)NR6R7,
2) aryl or heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3,
9) xe2x80x94S(O)mR4,
10) xe2x80x94C(O)NR6R7, or
11) C3-C6 cycloalkyl;
Z2 is selected from a bond, unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl, wherein the substituted aryl or substituted heteroaryl is substituted with one or more of:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) xe2x80x94S(O)mR4, or
g) xe2x80x94C(O)NR6R7,
2) aryl or heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3,
9) xe2x80x94S(O)mR4,
10) xe2x80x94C(O)NR6R7, or
11) C3-C6 cycloalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3or 4;
q is 1 or 2;
r is 0 to 5;
s is independently 0, 1, 2 or 3; and
t is 1, 2, 3 or 4;
or a pharmaceutically acceptable salt or stereoisomer thereof.
In a third embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula A: 
wherein:
R1a and R1d is independently selected from hydrogen and C1-C6 alkyl;
R1b, R1c and R1e are independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10Oxe2x80x94, xe2x80x94N(R10)2 or C2-C6 alkenyl, and
c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R10Oxe2x80x94 and xe2x80x94N(R10)2;
R4 is selected from C1-4 alkyl and C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6 and R7 are independently selected from H; C1-4 alkyl, C3-6 cycloalkyl, aryl and heterocycle, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by: unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R9 is selected from:
a) hydrogen,
b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, CN, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
R11 is independently selected from C1-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
A1 is selected from a bond, xe2x80x94C(O)13 , xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94, and S(O)m;
A2 is selected from a bond, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94, S(O)m and xe2x80x94C(R1d)2xe2x80x94;
V is selected from:
a) heteroaryl selected from imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, and
b) aryl;
W is a heterocycle selected from imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, or isoquinolinyl;
X and Y are independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, xe2x80x94NR10C(O)NR10xe2x80x94, xe2x80x94C(O)NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94, and S(O)m;
Z1 is selected from unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, wherein the substituted aryl or substituted heteroaryl is independently substituted with one or two of:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) xe2x80x94S(O)mR4, or
g) xe2x80x94C(O)NR6R7,
2) aryl or heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3,
9) xe2x80x94S(O)mR4,
10) xe2x80x94C(O)NR6R7, or
11) C3-C6 cycloalkyl;
Z2 is selected from a bond, unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl, wherein the substituted aryl or substituted heteroaryl is substituted independently with one or two of:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) xe2x80x94S(O)mR4, or
g) xe2x80x94C(O)NR6R7,
2) aryl or heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3,
9) xe2x80x94S(O)mR4,
10) xe2x80x94C(O)NR6R7, or
11) C3-C6 cycloalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 1 or 2;
r is 0 to 5;
s is independently 0, 1, 2 or 3; and
t is 1, 2, 3 or 4;
or a pharmaceutically acceptable salt or stereoisomer thereof.
In a fourth embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula B: 
wherein:
R1a, R1b and R1c are independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10Oxe2x80x94, xe2x80x94N(R10)2 or C2-C6 alkenyl, and
c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10Oxe2x80x94, or xe2x80x94N(R10)2;
R1e is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, cycloalkyl, alkenyl, alkynyl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(O)xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94,
c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, halogen, R10Oxe2x80x94, R4S(O)mxe2x80x94, R4S(O)2NR10xe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(O)xe2x80x94, CN, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, and R11OC(O)-NR10xe2x80x94;
or two R1es, on the same carbon atom may be combined to form xe2x80x94(CH2)vxe2x80x94;
R4 is selected from C1-4 alkyl and C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6 and R7 are independently selected from H; C1-6 alkyl, C3-6 cycloalkyl, C6-C10 multicyclic alkyl ring, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or two:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO, 
f) xe2x80x94SO2R11,
g) N(R10)2,
h) C3-6 cycloalkyl,
i) C6-C10 multicyclic alkyl ring; or
R8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R12Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by: unsubstituted or substituted aryl, C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R9a is hydrogen or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and unsubstituted or substituted aryl;
R11 is independently selected from C1-C6 alkyl and unsubstituted or substituted aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, unsubstituted or substituted benzyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, and C1-C6 alkyl substituted with unsubstituted or substituted aryl or unsubstituted or substituted heterocycle;
A1 is selected from a bond, xe2x80x94C(O)- and O;
V is selected from:
a) heteroaryl selected from imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, and
b) aryl;
X and Y are independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, xe2x80x94NR10C(O)NR10xe2x80x94, xe2x80x94C(O)NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94, and S(O)m;
Z1 is selected from unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is independently substituted with one or two of:
1) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) xe2x80x94S(O)mR4,
g) xe2x80x94C(O)NR6R7,
h) xe2x80x94Si(C1-4 alkyl)3, or
i) C1-4 perfluoroalkyl;
2) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3,
9) xe2x80x94S(O)mR4,
10) xe2x80x94OS(O)2R4,
11) xe2x80x94C(O)NR6R7,
12) xe2x80x94C(O)OR6, or
13) C3-C6 cycloalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5;
s is independently 0, 1, 2 or 3; and
t is 1, 2, 3 or 4;
or a pharmaceutically acceptable salt or stereoisomer thereof.
In a fifth embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula B: 
wherein:
R1a and R1e are independently selected from hydrogen or C1-C6 alkyl;
R1b and R1c is independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10Oxe2x80x94, xe2x80x94N(R10)2 or C2-C6 alkenyl, and
c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10Oxe2x80x94, or xe2x80x94N(R10)2;
R4 is selected from C1-4 alkyl and C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6 and R7 are independently selected from:
a) hydrogen,
b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10C(O)- or R10OC(O)- and
c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by: unsubstituted or substituted aryl, C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R9a is hydrogen or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and unsubstituted or substituted aryl;
R11 is independently selected from C1-C6 alkyl and unsubstituted or substituted aryl;
A1 is selected from a bond, xe2x80x94C(O)- and O;
V is selected from:
a) heteroaryl selected from imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, and
b) aryl;
X and Y are independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, xe2x80x94NR10C(O)NR10, xe2x80x94C(O)NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94, and S(O)m;
Z1 is selected from unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, wherein the substituted aryl or substituted heteroaryl is independently substituted with one or two of:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) xe2x80x94S(O)mR4, or
g) xe2x80x94C(O)NR6R7,
2) aryl or heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3,
9) xe2x80x94S(O)mR4,
10) xe2x80x94C(O)NR6R7, or
11) C3-C6 cycloalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5;
s is independently 0, 1, 2 or 3; and
t is 1, 2, 3 or 4;
or a pharmaceutically acceptable salt or stereoisomer thereof.
A preferred embodiment of the compounds of this invention is illustrated by the formula C-1:
wherein:
R1a, R1b and R1c are independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10Oxe2x80x94, xe2x80x94N(R10)2 or C2-C6 alkenyl, and
c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10Oxe2x80x94, or xe2x80x94N(R10)2;
R1e is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, cycloalkyl, alkenyl, alkynyl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(O)xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94,
c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, halogen, R10Oxe2x80x94, R4S(O)mxe2x80x94, R4S(O)2NR10xe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(O)xe2x80x94, CN, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, and R11OC(O)-NR10xe2x80x94;
or two R1es, on the same carbon atom may be combined to form xe2x80x94(CH2)vxe2x80x94;
R4 is selected from C1-4 alkyl and C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6 and R7 are independently selected from H; C1-6 alkyl, C3-6 cycloalkyl, C6-C10 multicyclic alkyl ring, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or two:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO, 
f) xe2x80x94SO2R11,
g) N(R10)2,
h) C3-6 cycloalkyl,
i) C6-C10 multicyclic alkyl ring; or
R8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R12Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by unsubstituted or substituted aryl, C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R9a is hydrogen or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, unsubstituted or substituted benzyl and unsubstituted or substituted aryl;
R11 is independently selected from C1-C6 alkyl and unsubstituted or substituted aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, unsubstituted or substituted benzyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, and C1-C6 alkyl substituted with unsubstituted or substituted aryl or unsubstituted or substituted heterocycle;
A1 is selected from a bond, xe2x80x94C(O)- and O;
V is phenyl or pyridyl;
X and Y are independently selected from: xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, xe2x80x94NR10C(O)NR10xe2x80x94, xe2x80x94C(O)NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94, and S(O)m;
Z1 is selected from unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or two of:
1) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) xe2x80x94S(O)mR4,
g) xe2x80x94C(O)NR6R7,
h) xe2x80x94Si(C1-4 alkyl)3, or
i) C1-4 perfluoroalkyl;
2) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3,
9) xe2x80x94S(O)mR4,
10) xe2x80x94OS(O)2R4,
11) xe2x80x94C(O)NR6R7,
12) xe2x80x94C(O)OR6, or
13) C3-C6 cycloalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5;
s is independently 0, 1, 2 or 3; and
t is 1, 2, 3 or 4;
or a pharmaceutically acceptable salt or stereoisomer thereof.
Another embodinent of the compounds of this invention is illustrated by the formula C: 
wherein:
R1a and R1e are independently selected from hydrogen and C1-C6 alkyl;
R1b and R1c is independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10Oxe2x80x94, xe2x80x94N(R10)2 or C2-C6 alkenyl, and
c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10Oxe2x80x94, or xe2x80x94N(R10)2;
R4 is selected from C1-4 alkyl and C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6 and R7 are independently selected from:
a) hydrogen,
b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10C(O)- or R10OC(O)- and
c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by unsubstituted or substituted aryl, C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R9a is hydrogen or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and unsubstituted or substituted aryl;
R11 is independently selected from C1-C6 alkyl and unsubstituted or substituted aryl;
A1 is selected from a bond, xe2x80x94C(O)- and O;
X and Y are independently selected from: xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, xe2x80x94NR10C(O)NR10xe2x80x94, xe2x80x94C(O)NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94, and S(O)m;
Z1 is selected from unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, wherein the substituted aryl or substituted heteroaryl is substituted with one or two of:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) xe2x80x94S(O)mR4, or
g) xe2x80x94C(O)NR6R7,
2) aryl or heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3,
9) xe2x80x94S(O)mR4,
10) xe2x80x94C(O)NR6R7, or
11) C3-C6 cycloalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5;
s is independently 0, 1, 2 or 3; and
t is 1, 2, 3 or 4;
or a pharmaceutically acceptable salt or stereoisomer thereof.
In another embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula D: 
wherein:
R1a, R1b and R1c are independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10Oxe2x80x94, xe2x80x94N(R10)2 or C2-C6 alkenyl, and
c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10Oxe2x80x94, or xe2x80x94N(R10)2;
R1e is independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(O)xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94,
c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(O)xe2x80x94, CN, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, and R11OC(O)-NR10xe2x80x94;
R4 is selected from C1-4 alkyl and C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6 and R7 are independently selected from H; C1-6 alkyl, C3-6 cycloalkyl, C6-C10 multicyclic alkyl ring, aryl, aroyl, arylsulfonyl, unsubstituted or substituted with one or two:
a) C1-4 alkoxy,
b) aryl,
c) halogen,
d) HO, 
f) xe2x80x94SO2R11,
g) N(R10)2,
h) C3-6 cycloalkyl,
i) C6-C10 multicyclic alkyl ring; or
R8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R12Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by unsubstituted or substituted aryl, C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R9a is hydrogen or methyl;
R10 and R12 are independently selected from hydrogen, C1-C6 alkyl, unsubstituted or substituted benzyl and unsubstituted or substituted aryl;
R11 is independently selected from C1-C6 alkyl and unsubstituted or substituted aryl;
A1 is selected from a bond, xe2x80x94C(O)- and O;
X and Y are independently selected from: xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, xe2x80x94NR10C(O)NR10xe2x80x94, xe2x80x94C(O)NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94, and S(O)m;
Z1 is selected from unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or two of:
1) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) xe2x80x94S(O)mR4,
g) xe2x80x94C(O)NR6R7,
h) xe2x80x94Si(C1-4 alkyl)3, or
i) C1-4 perfluoroalkyl;
2) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3,
9) xe2x80x94S(O)mR4,
10) xe2x80x94OS(O)2R4,
11) xe2x80x94C(O)NR6R7,
12) xe2x80x94C(O)OR6, or
13) C3-C6 cycloalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5;
s is independently 0, 1, 2 or 3; and
t is 1, 2, 3 or 4;
or a pharmaceutically acceptable salt or stereoisomer thereof.
In another embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula D: 
wherein:
R1a and R1e are independently selected from hydrogen and C1-C6 alkyl;
R1b and R1c is independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10Oxe2x80x94, xe2x80x94N(R10)2 or C2-C6 alkenyl, and
c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10Oxe2x80x94, or xe2x80x94N(R10)2;
R4 is selected from C1-4 alkyl and C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6 and R7 are independently selected from:
a) hydrogen,
b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10C(O)- or R10OC(O)- and
c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by unsubstituted or substituted aryl, C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R9a is hydrogen or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and unsubstituted or substituted aryl;
R11 is independently selected from C1-C6 alkyl and unsubstituted or substituted aryl;
A1 is selected from a bond, xe2x80x94C(O)- and O;
X and Y are independently selected from: xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, xe2x80x94NR10C(O)NR10xe2x80x94, xe2x80x94C(O)NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94, and S(O)m;
Z1 is selected from unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, wherein the substituted aryl or substituted heteroaryl is substituted with one or two of:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) xe2x80x94S(O)mR4, or
g) xe2x80x94C(O)NR6R7,
2) aryl or heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3,
9) xe2x80x94S(O)mR4,
10) xe2x80x94C(O)NR6R7, or
11) C3-C6 cycloalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5;
s is independently 0, 1, 2 or 3; and
t is 1, 2, 3 or 4;
or a pharmaceutically acceptable salt or stereoisomer thereof.
In further preferred embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula E: 
wherein:
R1a, R1b and R1c are independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10Oxe2x80x94, xe2x80x94N(R10)2 or C2-C6 alkenyl, and
c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10Oxe2x80x94, or xe2x80x94N(R10)2;
R1e is independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(O)xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94,
c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(O)xe2x80x94, CN, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, and R11OC(O)xe2x80x94NR10xe2x80x94;
R4 is selected from C1-4 alkyl and C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6 and R7 are independently selected from H; C1-6 alkyl, C3-6 cycloalkyl, C6-C10 multicyclic alkyl ring, aryl, aroyl, arylsulfonyl, unsubstituted or substituted with one or two:
a) C1-4 alkoxy,
b) aryl,
c) halogen,
d) HO, 
f) xe2x80x94SO2R11 
g) N(R10)2,
h) C3-6 cycloalkyl,
i) C6-C10 multicyclic alkyl ring; or
R8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R12Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by unsubstituted or substituted aryl, C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R9a is hydrogen or methyl;
R10 and R12 are independently selected from hydrogen, C1-C6 alkyl, unsubstituted or substituted benzyl and unsubstituted or substituted aryl;
R11 is independently selected from C1-C6 alkyl and unsubstituted or substituted aryl;
A1 is selected from a bond, xe2x80x94C(O)xe2x80x94 and O;
X and Y are independently selected from: xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, xe2x80x94NR10C(O)NR10xe2x80x94, xe2x80x94C(O)NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94, and S(O)m;
Z1 is selected from unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or two of:
1) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) xe2x80x94S(O)mR4,
g) xe2x80x94C(O)NR6R7,
h) xe2x80x94Si(C1-4 alkyl)3, or
i) C1-4 perfluoroalkyl;
2) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3,
9) xe2x80x94S(O)mR4,
10) xe2x80x94OS(O)2R4,
11) xe2x80x94C(O)NR6R7,
12) xe2x80x94C(O)OR6, or
13) C3-C6 cycloalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4; provided p is 2, 3 or 4 when X is xe2x80x94NR10C(O)xe2x80x94, xe2x80x94NR10C(O)NR10xe2x80x94, O, xe2x80x94N(R10)xe2x80x94 or N(R10)S(O)2xe2x80x94;
r is 0 to 5;
s is independently 0, 1, 2 or 3; and
t is 1, 2, 3 or 4;
or a pharmaceutically acceptable salt or stereoisomer thereof.
In another embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula E: 
wherein:
R1a and R1e are independently selected from hydrogen and C1-C6 alkyl;
R1b and R1c is independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10Oxe2x80x94, xe2x80x94N(R10)2 or C2-C6 alkenyl, and
c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10Oxe2x80x94, or xe2x80x94N(R10)2;
R4 is selected from C1-4 alkyl and C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6 and R7 are independently selected from:
a) hydrogen,
b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10C(O)xe2x80x94 or R10OC(O)xe2x80x94 and
c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by unsubstituted or substituted aryl, C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R9a is hydrogen or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and unsubstituted or substituted aryl;
R11 is independently selected from C1-C6 alkyl and unsubstituted or substituted aryl;
A1 is selected from a bond, xe2x80x94C(O)xe2x80x94 and O;
X and Y are independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, xe2x80x94NR10C(O)NR10xe2x80x94, xe2x80x94C(O)NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94, and S(O)m;
Z1 is selected from unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, wherein the substituted aryl or substituted heteroaryl is substituted with one or two of:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) xe2x80x94S(O)mR4, or
g) xe2x80x94C(O)NR6R7,
2) aryl or heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3,
9) xe2x80x94S(O)mR4,
10) xe2x80x94C(O)NR6R7, or
11) C3-C6 cycloalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4; provided p is 2, 3 or 4 when X is xe2x80x94NR10C(O)xe2x80x94, xe2x80x94NR10C(O)NR10xe2x80x94, O, xe2x80x94N(R10)xe2x80x94 or N(R10)S(O)2xe2x80x94;
r is 0 to 5;
s is independently 0, 1, 2 or 3; and
t is 1, 2, 3 or 4;
or a pharmaceutically acceptable salt or stereoisomer thereof.
Examples of the compounds of the invention are:
20-n-Butyl-17,18,19,20-tetrahydro-17-[2,4-dimethoxybenzyl]-18-oxo-5H-6,10:12,16-dimetheno-21H-imidazo[4,3-l][1,7,10,13]oxatriazacyclononadecine-9-carbonitrile (Compound 1)
20-n-Butyl-17,18,19,20-tetrahydro-18-oxo-5H-6,10:12,16-dimetheno-21H-imidazo[4,3-l][1,7,10,13]oxatriazacyclononadecine-9-carbonitrile, (Compound 2)
20-n-Butyl-17,18,19,20-tetrahydro-18 -oxo-17-[3-(trifluoromethyl)phenyl]-5H-6,10:12,16-dimetheno-21H-imidazo[4,3-l][1,7,10,13]oxatriazacyclononadecine-9-carbonitrile (Compound 3)
19,20,21,22-Tetrahydro-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecine-9-carbonitrile 19,20,21,22-Tetrahydro-19-oxo-17H-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile
(20R)-19,20,21,22-Tetrahydro-20-methyl-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecine-9-carbonitrile
(20S)-19,20,21,22-Tetrahydro-20-methyl-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecine-9-carbonitrile
(20R)-20-Benzyl-19,20,21,22-tetrahydro-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclo-octadecine-9-carbonitrile
(20S)-20-Benzyl-19,20,21,22-tetrahydro-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclo-octadecine-9-carbonitrile
(20R)-19,20,21,22-Tetrahydro-19-oxo-20-(3-pyridylmethyl)-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecine-9-carbonitrile
(20R)-19,20,21,22-Tetrahydro-19-oxo-20-(thiophen-2-ylmethyl)-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecine-9-carbonitrile
(20R)-19,20,22,23-Tetrahydro-20-methyl-19,22-dioxo-5H,21H-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecine-9-carbonitrile
(20R)-20-Benzyl-19,20,22,23-tetrahydro-19,22-dioxo-5H,21H-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]-oxatriazacyclononadecine-9-carbonitrile
(20R)-19,20,21,22-Tetrahydro-18,20-dimethyl-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecine-9-carbonitrile
(20S)-19,20,21,22-Tetrahydro-18,20-dimethyl-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecine-9-carbonitrile
19,20,21,22-Tetrahydro-18-methyl-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecine-9-carbonitrile
19,20,21,22-Tetrahydro-18,21-dimethyl-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecine-9-carbonitrile
(20R)-19,20,21,22-Tetrahydro-18,20,21-trimethyl-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecine-9-carbonitrile
(20S)-19,20,21,22-Tetrahydro-18,20,21-trimethyl-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecine-9-carbonitrile
19,20,21,22-Tetrahydro-21-methyl-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecine-9-carbonitrile
(20R)-19,20,21,22-Tetrahydro-20,21-dimethyl-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecine-9-carbonitrile
(20S)-19,20,21,22-Tetrahydro-20,21-dimethyl-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecine-9-carbonitrile
19,20,21,22-Tetrahydro-21-methyl-19-oxo-17H-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile
(20R)-20-Benzyl-19,20,21,22-tetrahydro-21-methyl-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecine-9-carbonitrile
(20S)-20-Benzyl-19,20,21,22-tetrahydro-21-methyl-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecine-9-carbonitrile
(20R)-20,21-Dibenzyl-19,20,21,22-tetrahydro-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecine-9-carbonitrile
(20S)-20,21-Dibenzyl-19,20,21,22-tetrahydro-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclo-octadecine-9-carbonitrile
21-Benzyl-19,20,21,22-tetrahydro-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclo-octadecine-9-carbonitrile
(20R)-21-Benzyl-19,20,21,22-tetrahydro-20-methyl-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecine-9-carbonitrile
18,19,20,21,22,23-Hexahydro-18-oxo-5H-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,7,10,13]oxatriazacyclononadecine-9-carbonitrile
18,19,20,21,22,23-Hexahydro-18,21-dioxo-5H-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,7,10,13]oxatriazacyclononadecine-9-carbonitrile
19,20,21,22,23,24-Hexahydro-18,23-dioxo-5H-12,14-etheno-6,10-18H-methenobenz[d]imidazo[4,3-m][1,7,10,14]oxatriazacycloeicosine-9-carbonitrile
or the pharmaceutically acceptable salts thereof.
Specific example of the compounds of the instant invention include: 
(20R)-20-Benzyl-19,20,21,22-tetrahydro-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclo-octadecine-9-carbonitrile 
19,20,21,22-Tetrahydro-21-methyl-19-oxo-17H-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile 
19,20,21,22-Tetrahydro-18,21-dimethyl-19-oxo-5H-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclo-octadecine-9-carbonitrile 
18,19,20,21,22,23-Hexahydro-18-oxo-5H-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,7,10,13]oxatriazacyclononadecine-9-carbonitrile
or a pharmaceutically acceptable salt or stereoisomer thereof.
The compounds of the present invention may have asymmetric centers, chiral axes and chiral planes, and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. (See E. L. Eliel and S. H. Wilen Sterochemistry of Carbon Compounds (John Wiley and Sons, New York 1994), in particular pages 1119-1190) When any variable (e.g. aryl, heterocycle, R1a, R6 etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurence. Also, combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. xe2x80x9cHalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein means fluoro, chloro, bromo and iodo.
Preferably, alkenyl is C2-C6 alkenyl.
Preferably, alkynyl is C2-C6 alkynyl.
As used herein, xe2x80x9ccycloalkylxe2x80x9d is intended to include cyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Preferably, cycloalkyl is C3-C10 cycloalkyl. Examples of such cycloalkyl elements include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
As used herein, the terms xe2x80x9cC6-C10 multicyclic alkyl ringxe2x80x9d and xe2x80x9cC6-C10 multicyclic ringxe2x80x9d are intended to include polycyclic saturated and unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of such multicyclic ring groups includes, but are not limited to: 
Preferably, C6-C10 multicyclic alkyl ring is adamantyl.
As used herein, xe2x80x9carylxe2x80x9d is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. The term heterocycle or heterocyclic, as used herein, includes heteroaryl moieties. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
As used herein, xe2x80x9cheteroarylxe2x80x9d is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S. Examples of such heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, and thienyl.
As used herein, unless otherwise specifically defined, substituted alkyl, substituted cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted heteroaryl, substituted arylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycle include moieties containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound. Preferably, such substituents are selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(C1-C6 alkyl)2, NO2, CN, (C1-C6 alkyl)Oxe2x80x94, (aryl)Oxe2x80x94, xe2x80x94OH, (C1-C6 alkyl)S(O)mxe2x80x94, (C1-C6 alkyl)C(O)NHxe2x80x94, H2Nxe2x80x94C(NH)xe2x80x94, (C1-C6 alkyl)C(O)xe2x80x94, (C1-C6 alkyl)OC(O)xe2x80x94, N3, (C1-C6 alkyl)OC(O)NHxe2x80x94, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and C1-C20 alkyl.
Preferably, as used herein in the definition of R6 and R7, the substituted C1-6 alkyl, substituted C2-6 alkenyl, substituted C2-6 alkynyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroarylsulfonyl, substituted heterocycle and substituted C6-10 multicyclic alkyl ring, include moieties containing from 1 to 3 substitutents in addition to the point of attachment to the rest of the compound.
The moiety formed when, in the definition of R1a, R1b, R1c, R1d and R1e, two R1as, two R1bs, two R1cs, two R1ds or two R1es, on the same carbon atom are combined to form xe2x80x94(CH2)vxe2x80x94 is illustrated by the following: 
Lines drawn into the ring systems from substituents (such as from R8, R9 etc.) indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.
Preferably, R1a and R1b are independently selected from: hydrogen, xe2x80x94N(R10)2, R10C(O)NR10xe2x80x94 or unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted phenyl, xe2x80x94N(R10)2, R10Oxe2x80x94 and R10C(O)NR10xe2x80x94. More preferably, R1a and R1b are hydrogen.
Preferably, R1c is independently selected from: hydrogen, or unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted phenyl, xe2x80x94N(R10)2, R10Oxe2x80x94 and R10C(O)NR10xe2x80x94.
Preferably, R1e is selected from:
a) hydrogen,
b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10Oxe2x80x94, xe2x80x94N(R10)2, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(O)xe2x80x94, or R10OC(O)xe2x80x94, and
c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, halo, perfluoroalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10Oxe2x80x94, R4S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(O)xe2x80x94, CN, N3, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R4S(O)2NR10xe2x80x94, xe2x80x94S(O)2N(R10)2, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, xe2x80x94N(R10)2, and R11OC(O)xe2x80x94NR10xe2x80x94;
or two R1es on the same carbon atom may be combined to form xe2x80x94(CH2)vxe2x80x94.
Preferably, R4 is C1-C6 alkyl.
Preferably, R6 and R7 is selected from: hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.
Preferably, R9 is hydrogen or methyl.
Preferably, R10 is selected from H, C1-C6 alkyl and benzyl.
Preferably, A1 and A2 are independently selected from a bond, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94 and xe2x80x94N(R10)S(O)2xe2x80x94.
Preferably, V is selected from heteroaryl and aryl. More preferably, V is phenylor pyridyl.
Preferably, X and Y are independently selected from xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94 and xe2x80x94N(R10)S(O)2xe2x80x94.
Preferably, Z1 and Z2 are independently selected from unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl. More preferably, Z1 and Z2 are independently selected from unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted pyridyl, unsubstituted or substituted furanyl and unsubstituted or substituted thienyl. Still more preferably, Z1 is selected from unsubstituted or substituted phenyl and unsubstituted or substituted naphthyl. Still more preferably, Z2 is selected from a bond and unsubstituted or substituted phenyl.
Preferably, W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyrrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.
Preferably, n is 0, 1, or 2.
Preferably, r is 1 or 2.
Preferably p is 1, 2 or 3.
Preferably s is 0 or 1.
Preferably, the moiety 
is selected from: 
wherein R9a and R9b are independently selected from hydrogen or methyl.
It is intended that the definition of any substituent or variable (e.g., R1a, R9, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, xe2x80x94N(R10)2 represents xe2x80x94NHH, xe2x80x94NHCH3, xe2x80x94NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-14, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Substituents Rsub and Rsubxe2x80x2, as shown in the Schemes, represent the substituents on Z1 and Z2 and other moieties of the instant compounds; however their point of attachment to the ring is illustrative only and is not meant to be limiting.
These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes.
Synopsis of Schemes 1-14:
The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures. In Scheme 1, for example, the synthesis of a key intermediate in the preparation of macrocyclic compounds of the instant invention containing the preferred benzylimidazolyl moiety is outlined. A suitably substituted fluorotoluene I is brominated and reacted with an imidazolylmethyl acetate to form the intermediate II. Reduction, followed by oxidation provided the aldehyde III which is then reductively alkylated with a suitably substituted amine to provide the intermediate IV.
Scheme 2 illustrates the synthesis of a compound of the instant invention which utilizes intermediate IV. Thus, a suitably substituted hydroxyanaline V is N-protected, for example with by reductive alkylation with 2,4-dimethoxybenzaldehyde, and the resulting secondary amine is reacted with a suitably substituted chloroacetyl chloride to provide intermediate VI. Intermediate VI is then reacted with the imidazolylmethylamine IV to provide the protected amide VII. Intermediate VII may then undergo a cesium carbonate nucleophillic aromatic substitution reaction resulting in an intramolecular cyclization to yield compound VIII of the instant invention. This cyclization reaction depends on the presence of an electronic withdrawing moiety (such as nitro, cyano, and the like) either ortho or para to the fluorine atom. Compound VIII may be N-deprotected to provide instant compound IX, which may itself be further elaborated, for example by boronic acid coupling to give compound X of the instant invention.
Syntheses of compounds of the instant invention wherein the linker xe2x80x9cXxe2x80x9d is an ether linkage are illustrated in Scheme 3. Thus, the protected amide VI is reacted with a suitably substituted sodium benzylimidazolyl methoxide to provide intermediate XI, intramolecular cyclization as previously described, followed by deprotection provides the instant compound XII, which can be further elaborated as shown.
Scheme 4 illustrates syntheses of instant compounds wherein the linker xe2x80x9cXxe2x80x9d is an amido linkage. Thus, the primary amine XIII, homologous to intermediate IV is reacted with a suitably substituted bromoacetyl bromide, followed by a reaction with a nucleophile, such as a suitably substituted O-protected hydroxythiophenol. The resulting intermediate XIV is deprotected and intramolecular cyclization as previously described provides compound XV of the instant invention. The sulfur moiety in compound XV also may be oxidized to provide instant compound XVI.
Scheme 5 illustrates the synthetic strategy that is employed when the R8 substitutent is not an electronic withdrawing moiety either ortho or para to the fluorine atom. In the absence of the electronic withdrawing moiety, the intramolecular cyclization can be accomplished via an Ullmann reaction. Thus, the previously described aldehyde III can be converted to the homologous amine XVII. Amine XVII is then reacted with the previously described chloroacetamide VI to provide intermediate XVIII. Intramolecular cyclization may then be affected under Ullmann reaction to provide intermediate XIX, which may be deprotected and reduced to provide the diamino macrocycle of the instant invention XX.
Schemes 6-9 illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art.
Scheme 10 depicts the synthesis of compounds of the instant invention having an imidazolyl moiety incorporated into the macrocyclic ring via different points of attachement. Activated zinc is added to a fluoroaryl methylhalide in THF to form the arylmethyl zinc halide, which is subsequently coupled to an N-protected 4-iodoimidazole to give compound XXI. Regiospecfic alkylation of the imidazole ring is accomplished with ethyl bromoacetate, with subsequent methanolysis of the intermediate imidazolium salt giving XXII. Elaboration of XXII to the primary amine proceeds through standard chemistry. Alkylation of the amine with suitably substituted N-aryl chloroacetamide (similar to the reaction illustrated in Scheme 5) provides the intermediate amide, which can then undergo cyclization as described above to provide the compound of the instant invention XXIII.
Schemes 11-14 illustrate methods of synthesizing compounds of the instant invention that comprise other permutations of the xe2x80x94Xxe2x80x94(CR1e2)txe2x80x94Yxe2x80x94 moiety. 
In a preferred embodiment of the instant invention the compounds of the invention are selective inhibitors of farnesyl-protein transferase. A compound is considered a selective inhibitor of farnesyl-protein transferase, for example, when its in vitro farnesyl-protein transferase inhibitory activity, as assessed by the assay described in Example 33, is at least 100 times greater than the in vitro activity of the same compound against geranylgeranyl-protein transferase-type I in the assay described in Example 34. Preferably, a selective compound exhibits at least 1000 times greater activity against one of the enzymatic activities when comparing geranylgeranyl-protein transferase-type I inhibition and farnesyl-protein transferase inhibition.
It is also preferred that the selective inhibitor of farnesyl-protein transferase is further characterized by:
a) an IC50 (a measure of in vitro inhibitory activity) for inhibition of the prenylation of newly synthesized K-Ras protein more than about 100-fold higher than the EC50 for the inhibition of the farnesylation of hDJ protein.
When measuring such IC50s and EC50s the assays described in Example 38 may be utilized.
It is also preferred that the selective inhibitor of farnesyl-protein transferase is further characterized by:
b) an IC50 (a measurement of in vitro inhibitory activity) for inhibition of K4B-Ras dependent activation of MAP kinases in cells at least 100-fold greater than the IC50 for inhibition of the farnesylation of the protein hDJ in cells.
It is also preferred that the selective inhibitor of farnesyl-protein transferase is further characterized by:
c) an IC50 (a measurement of in vitro inhibitory activity) against H-Ras dependent activation of MAP kinases in cells at least 1000 fold lower than the inhibitory activity (IC50) against H-ras-CVLL (SEQ.ID.NO.: 1) dependent activation of MAP kinases in cells.
When measuring Ras dependent activation of MAP kinases in cells the assays described in Example 37 may be utilized.
In another preferred embodiment of the instant invention the compounds of the invention are dual inhibitors of farnesyl-protein transferase and geranylgeranyl-protein transferase type I. Such a dual inhibitor may be termed a Class II prenyl-protein transferase inhibitor and will exhibit certain characteristics when assessed in in vitro assays, which are dependent on the type of assay employed.
In a SEAP assay, such as described in Examples 37, it is preferred that the dual inhibitor compound has an in vitro inhibitory activity (IC50) that is less than about 12 xcexcM against K4B-Ras dependent activation of MAP kinases in cells.
The Class II prenyl-protein transferase inhibitor may also be characterized by:
a) an IC50 (a measurement of in vitro inhibitory activity) for inhibiting K4B-Ras dependent activation of MAP kinases in cells between 0.1 and 100 times the IC50 for inhibiting the farnesylation of the protein hDJ in cells; and
b) an IC50 (a measurement of in vitro inhibitory activity) for inhibiting K4B-Ras dependent activation of MAP kinases in cells greater than 5-fold lower than the inhibitory activity (IC50) against expression of the SEAP protein in cells transfected with the pCMV-SEAP plasmid that constitutively expresses the SEAP protein.
The Class II prenyl-protein transferase inhibitor may also be characterized by:
a) an IC50 (a measurement of in vitro inhibitory activity) against H-Ras dependent activation of MAP kinases in cells greater than 2 fold lower but less than 20,000 fold lower than the inhibitory activity (IC50) against H-ras-CVLL (SEQ.ID.NO.: 1) dependent activation of MAP kinases in cells; and
b) an IC50 (a measurement of in vitro inhibitory activity) against H-ras-CVLL dependent activation of MAP kinases in cells greater than 5-fold lower than the inhibitory activity (IC50) against expression of the SEAP protein in cells transfected with the pCMV-SEAP plasmid that constitutively expresses the SEAP protein.
The Class II prenyl-protein transferase inhibitor may also be characterized by:
a) an IC50 (a measurement of in vitro inhibitory activity) against H-Ras dependent activation of MAP kinases in cells greater than 10-fold lower but less than 2,500 fold lower than the inhibitory activity (IC50) against H-ras-CVLL (SEQ.ID.NO.: 1) dependent activation of MAP kinases in cells; and
b) an IC50 (a measurement of in vitro inhibitory activity) against H-ras-CVLL dependent activation of MAP kinases in cells greater than 5 fold lower than the inhibitory activity (IC50) against expression of the SEAP protein in cells transfected with the pCMV-SEAP plasmid that constitutively expresses the SEAP protein.
A method for measuring the activity of the inhibitors of prenyl-protein transferase, as well as the instant combination compositions, utilized in the instant methods against Ras dependent activation of MAP kinases in cells is described in Example 37.
In yet another embodiment, a compound of the instant invention may be a more potent inhibitor of geranylgeranyl-protein transferase-type I than it is an inhibitor of farnesyl-protein transferase.
The instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors. Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e., neurofibromin (NF-1), neu, src, abl, lck, fyn) or by other mechanisms.
The compounds of the instant invention inhibit prenyl-protein transferase and the prenylation of the oncogene protein Ras. The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575-4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of vision deficit related to retinal vascularization.
The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment. For example, a component of NF-1 is a benign proliferative disorder.
The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J. S. Glenn et al. Science, 256:1331-1333 (1992).
The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1:541-545(1995).
The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D. L. Schaffner et al. American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al. FASEB Journal, 2:A3160 (1988)).
The instant compounds may also be useful for the treatment of fungal infections.
The instant compounds may also be useful as inhibitors of proliferation of vascular smooth muscle cells and therefore useful in the prevention and therapy of arteriosclerosis and diabetic vascular pathologies.
The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinylpyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a water soluble taste masking material such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, ahard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring agents, preservatives and antioxidants.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous solutions. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution.
The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.
The injectable solutions or microemulsions may be introduced into a patient""s blood-stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS(trademark) model 5400 intravenous pump.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Compounds of Formula A may also be administered in the form of a suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula A are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
The compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, sex and response of the individual patient, as well as the severity of the patient""s symptoms.
In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
The compounds of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, the compounds of the instant invention may also be co-administered with other well known cancer therapeutic agents that are selected for their particular usefulness against the condition that is being treated. Included in such combinations of therapeutic agents are combinations of the instant prenyl-protein transferase inhibitors and an antineoplastic agent. It is also understood that such a combination of antineoplastic agent and sinhibitor of prenyl-protein transferase may be used in conjunction in with other methods of treating cancer and/or tumors, including radiation therapy and surgery.
Examples of an antineoplastic agent include, in general, microtubule-stabilizing agents (such as paclitaxel, also known as Taxol(copyright)), docetaxel (also known as Taxotere(copyright)), epothilone A, epothilone B, desoxyepothilone A, desoxyepothilone B or their derivatives); microtubule-disruptor agents; alkylating agents, anti-metabolites; epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes; biological response modifiers and growth inhibitors; hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors and antibodies (such as trastuzumab (Herceptin(trademark))).
Example classes of antineoplastic agents include, for example, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the taxanes, the epothilones, discodermolide, the pteridine family of drugs, diynenes and the podophyllotoxins. Particularly useful members of those classes include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel, trastuzumab (Herceptin(trademark)) and the like. Other useful antineoplastic agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.
The preferred class of antineoplastic agents is the taxanes and the preferred antineoplastic agent is paclitaxel.
Radiation therapy, including x-rays or gamma rays which are delivered from either an externally applied beam or by implantation of tiny radioactive sources, may also be used in combination with the instant inhibitor of prenyl-protein transferase alone to treat cancer.
Additionally, compounds of the instant invention may also be useful as radiation sensitizers, as described in WO 97/38697, published on Oct. 23, 1997, and herein incorporated by reference.
The instant compounds may also be useful in combination with other inhibitors of parts of the signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Thus, the instant compounds may be utilized in combination with farnesyl pyrophosphate competitive inhibitors of the activity of farnesyl-protein transferase or in combination with a compound which has Raf antagonist activity. The instant compounds may also be co-administered with compounds that are selective inhibitors of geranylgeranyl protein transferase.
In particular, if the compound of the instant invention is a selective inhibitor of farnesyl-protein transferase, co-administration with a compound(s) that is a selective inhibitor of geranylgeranyl protein transferase may provide an improved therapeutic effect.
In particular, the compounds disclosed in the following patents and publications may be useful as farnesyl pyrophosphate-competitive inhibitor component of the instant composition: U.S. Ser. Nos. 08/254,228 and 08/435,047. Those patents and publications are incorporated herein by reference.
In practicing methods of this invention, which comprise administering, simultaneously or sequentially or in any order, two or more of a protein substrate-competitive inhibitor and a farnesyl pyrophosphate-competitive inhibitor, such administration can be orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration. It is preferred that such administration be orally. It is more preferred that such administration be orally and simultaneously. When the protein substrate-competitive inhibitor and farnesyl pyrophosphate-competitive inhibitor are administered sequentially, the administration of each can be by the same method or by different methods.
The instant compounds may also be useful in combination with an integrin antagonist for the treatment of cancer, as described in U.S. Ser. No. 09/055,487, filed Apr. 6, 1998, which is incorporated herein by reference.
As used herein the term an integrin antagonist refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to an integrin(s) that is involved in the regulation of angiogenisis, or in the growth and invasiveness of tumor cells. In particular, the term refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the xcex1vxcex23 integrin, which selectively antagonize, inhibit or counteract binding of a physiological ligand to the xcex1vxcex25 integrin, which antagonize, inhibit or counteract binding of a physiological ligand to both the xcex1vxcex23 integrin and the xcex1vxcex25 integrin, or which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells. The term also refers to antagonists of the xcex11xcex21, xcex12xcex21, xcex15xcex21, xcex16xcex21 and xcex16xcex24 integrins. The term also refers to antagonists of any combination of xcex1vxcex23 integrin, xcex1vxcex25 integrin, xcex11xcex21, xcex12xcex21, xcex15xcex21, xcex16xcex21 and xcex16xcex24 integrins. The instant compounds may also be useful with other agents that inhibit angiogenisis and thereby inhibit the growth and invasiveness of tumor cells, including, but not limited to angiostatin and endostatin.
Similarly, the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-1, restenosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections.
If formulated as a fixed dose, such combination products employ the combinations of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range. Combinations of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a multiple combination formulation is inappropriate.
The compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of farnesyl-protein transferase (FPTase) in a composition. Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain farnesyl-protein transferase and quantitating the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention. The concentration of a sufficiently potent inhibitor (i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel) required to inhibit the enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample.